Toxicant exposures early in life adversely affect health outcomes in both animals and humans, in part due to epigenetic mechanisms (e.g. DNA methylation). Studies also indicate that exposures' impact on the epigenome can be tissue and even cell specific. Yet, epigenetic epidemiology analysis of toxicants is often limited to biologically available or surrogate (e.g. blood, saliva) samples, which serve as proxies for epigenetic status in tissues targeted by exposures. While methylation of peripheral DNA may not mirror that of all tissues, it has been used as a biomarker associated with both disease and exposures. Using bisphenol A and phthalates (e.g. DEHP) as representative toxicants, our overall objective is to utilize mouse models to evaluate tissue- and cell-specific epigenetic alterations associated with perinatal exposures and disease outcomes, including tissues not feasibly assessed in humans. We leverage resources by utilizing tissues funded as part of the Michigan NIEHS/EPA-funded Children's Environmental Health P01 Center in which epigenetic analysis in target tissues focuses on candidate metastable epialleles and imprinted genes, two sets of loci most vulnerable to environmental changes. Within TaRGET II U01, we will extend analysis genome- wide to 11 tissue and cell types to map DNA methylation (5mC), hydroxymethylation (5hmC), and gene expression in an effort to inform epigenetic epidemiology studies with an environmental focus. We use sample sizes powered to detect sex differences and conduct methylome and transcriptome analyses immediately following perinatal exposure at post-natal day 22 in target tissues from the three germ layers (brain & breast from ectoderm, kidney from mesoderm, & liver from endoderm) and in surrogate tissues of human relevance (hair, peripheral blood leukocytes, & stool), as well as longitudinally at 8 months of age to identify exposure- dependent epigenetic changes that persist into adulthood. Capitalizing on our team's expertise in cell-specific epigenetics, we also include 4 purified cell populations to furthr compare target cells to surrogates. Ultimately, we seek to identify a subset of tissue-independent labile genes, which represent regions of the epigenome vulnerable early in life, and may be interrogated, with the use of surrogate tissues.